1. Field of the Invention
The present invention relates to a protein composition of matter and a method for the treatment of chronic pain, especially to the treatment of heretofore intractable pain as associated with advanced cancer. The pain associated with neurological conditions, rheumatoid arthritis, viral infections and lesions may also respond to treatment with the present invention. The composition consists of an alpha-neurotoxin in acceptable carrier base for either parenteral, oral or topical administration.
2. Description of the Prior Art
Research into the pharmacological properties of natural products led to the identification of many compounds with a potent biological activity, which can result in clinically useful therapeutic agents (Verdine, 1996). Plant, microbial and animal toxins are of particular interest, due to their strong pharmacological activity and their selectivity for the site of action. They can be employed directly as therapeutic agents or can serve as starting points for drug design (Harvey et al., 1998).
Bee venom has been employed for centuries to relieve rheumatism and recent studies have shown the product to have useful analgesic properties that support the clinical observations. Snake venom also found extensive use as a therapeutic including pain relief (Williams, 1960). In Van Esveld's 1936 publication “Preparation of Cobratoxin for clinical purposes, especially for the treatment of cancer pains” and by reference to other publications of the same era namely Macht (1936, PNAS 22, pg 61-71) the term cobratoxin was employed in lieu of cobra venom. Cobratoxin, as a distinct neurotoxin, would not be isolated for several decades. Macht's description for the preparation of venom for clinical administration is quite similar to that of Van Esveld, where he describes the preparation of several venoms for use in the treatment of cancer-associated pain: Naja haje, Naja naja and Naja tripudian. Naja tripudian, the venom source for Van Esveld, was often a misidentified species and most often associated with Asian spitting snakes. Spitting snakes are a very poor source of cobratoxin regardless of their geographic location, more likely the neurotoxic component was cobrotoxin, and often tend to be more cytotoxic than neurotoxic. The use of venoms have fallen out of favor with the scientific community.
U.S. Pat. No. 5,364,842 describes the use of omega-conopeptides having defined binding/inhibitory properties in the treatment of chronic pain. In that patent is described omega-conopeptides having related inhibitory and binding activities that enhance the effects of opioid compounds in producing analgesia in mammalian subjects. In addition, these compounds may also produce analgesia in the absence of opioid treatment. Another requisite property of anti-nociceptive omega-conotoxin compounds, in accordance with the invention, is their ability to specifically inhibit depolarization-evoked and calcium-dependent neuro-transmitter release from neurons. In the case of anti-nociceptive omega-conopeptides, inhibition of electrically stimulated release of acetylcholine at the myenteric plexus of the guinea pig ileum is predictive of anti-nociceptive activity. U.S. Pat. No. 6,399,574 similarly describes the use of conantokin peptides which are antagonists of the NMDA receptor. However, these peptides must be delivered intrathecally in order to be effective.
There are several neurotoxins with different biological functions and mechanisms of action in snake venoms. Crotamine from the South American rattlesnake (Crotalus durissus terrificus), a myonecrotic toxin, was reported to produce analgesia in mouse models of pain that suggested having a potency up to 30 times greater than morphine (Mancin et al., 1998). Postsynaptic neurotoxins are commonly found in the venoms of Hydrophiidae and Elapidae, and can be divided into two types: short-chain alpha-neurotoxin (60-62 residues and four disulfides bonds)[1] and long-chain alpha-neurotoxin (66-74 residues and five disulfides bonds)[3]. Both short- and long-chain postsynaptic alpha-neurotoxins have a similar biological property; namely, binding to acetylcholine receptors (AchR). In animal models, Cobrotoxin, a short-chain neurotoxin with high affinity for muscle type AchRs, produced strong analgesic effects through an opiate-independent mechanism (Chen and Robinson, 1990). Cobrotoxin is sold in China as a component of an analgesic formulation.
Other references of interest include two patents, Haast, U.S. Pat. No. 4,341,762; Cosford, et al., U.S. Pat. No. 5,585,388, which claims compounds as modulators of acetylcholine receptors. Literature references of interest are: Chuang L. Y., Lin S. R., Chang S. F. and Chang C. C. Toxicon 27:211-219 (1989); Dierks R. E., Murphy F. A., and Harrison A. K. Am. J. Pathol. 54: 251-274 (1969); Tsiang H., de la Porte S., Ambroise D. J., Derer M. And Koenig J.; J. Neuropathol. Exp. Neurol. 45: 28-42; Tu A. T.; Ann. Rev. Biochem. 42:235-258(1973); Carstens E, Anderson K A, Simons C T, Carstens M I, Jinks S L. Psychopharmacology (Berl) 2001 August; 157(1):40-5 “Analgesia induced by chronic nicotine infusion in rats: differences by gender and pain test.”; Chen, R., Robinson, S E. Life Sci 1990; 47:1949-1954. “Effect of cholinergic manipulations on the analgesic response to cobrotoxin in mice.”; Damaj, M. I., Fei-Yin, M., Dukat, M., Glassco, W., Glennon, R. A. and Martin, B. R., JPET 1998 284:1058-1065, “Antinociceptive Responses to Nicotinic Acetylcholine Receptor Ligands after Systemic and Intrathecal Administration in Mice.”; Damaj M I, Meyer E M, Martin B R. Neuropharmacology 2000 October; 39(13):2785-91 “The antinociceptive effects of alpha7 nicotinic agonists in an acute pain model.”; Decker M W, Meyer M D, Sullivan J P. Expert Opin Investig Drugs 2001 October; 10(10):1819-30 “The therapeutic potential of nicotinic acetylcholine receptor agonists for pain control.”; Irnaten M, Wang J, Venkatesan P, Evans C, K Chang K S, Andresen M C, Mendelowitz D. Anesthesiology 2002 March; 96(3):667-74 “Ketamine inhibits presynaptic and postsynaptic nicotinic excitation of identified cardiac parasympathetic neurons in nucleus ambiguus.”; Kwon, Y. B., Kim, J. H., Yoon, J. H., Lee, J. D., Han, H. J., Mar, W. C., Beitz, A. J., Lee, J. H. Am J Chin Med 2001; 29(2):187-99 “The analgesic efficacy of bee venom acupuncture for knee osteoarthritis: a comparative study with needle acupuncture.”, Lieb K, Treffurth Y, Berger M, Fiebich B L. Neuropsychobiology 2002; 45 Suppl 1:2-6 “Substance P and affective disorders: new treatment opportunities by neurokinin 1 receptor antagonists?”; Mancin, A., Soares, A., Andriao-Escarso, S., Faca, V., Greene, L., Zuccolotto, S., Pela, I., Giglio, J. Toxicon. 36(12):1927-1937 (1998) “The Analgesic Activity of Crotamine, A Neurotoxin From Crotalus durissus terrificus (South Anerican Rattlesnake) Venom: A Biochemical and Pharmacological Study”; Miller, K. D., Miller, G. G., Sanders, M. and Fellowes, O., “Inhibition of virus-induced plaque formation by atoxic derivatives of purified cobra neurotoxins”, (1977) Biochim. Biophys. Acta., 496, 192-196; Min, C. K., Owens, J., Weiland, G. A. Mol Pharmacol 1994 February; 45(2):221-7 “Characterization of the binding of [3H]substance P to the nicotinic acetylcholine receptor of Torpedo electroplaque.”; Schaible H G, Ebersberger A, Von Banchet G S. Ann N Y Acad Sci 2002 June; 966:343-354 “Mechanisms of Pain in Arthritis.”; Schmidt B L, Tambeli C H, Gear R W, Levine J D. Neuroscience 2001; 106(1):129-36 “Nicotine withdrawal hyperalgesia and opioid-mediated analgesia depend on nicotine receptors in nucleus accumbens.”; Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I. Br J Pharmacol 2002 May; 136(2):207-16 “Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha7 receptors.”; Williams, E. Y., J Natl Med Assoc. 1960 September; 52:327-8. “Treatment of trigeminal neuralgia with cobra venom.”